I. Field of the Invention
The present invention relates generally to the fields of cancer biology and biochemistry. More particularly, the present invention is directed to a method of cancer chemotherapy in mammals.
II. Description of Related Art
1. NSAIDS
There is an increasing body of experimental and epidemiological data suggesting that aspirin, and some other non-steroidal anti-inflammatory drugs (NSAID), exert a chemopreventive action on colorectal cancers and maybe also on stomach, esophagus (Thun et al., 1993) and even bladder (Earnest et al., 1992) cancers. Aspirin, ibuprofen, piroxicam (Reddy et al., 1990; Singh et al., 1994), indomethacin (Narisawa, 1981), and sulindac (Piazza et al., 1997; Rao et al., 1995), effectively inhibit colon carcinogenesis in the AOM-treated rat model and flurbiprofen has demonstrated anti-tumor effects in the APC(Min)+ mouse model (Wechter et al., 1997). NSAIDs also inhibit the development of tumors harboring an activated Ki-ras (Singh and Reddy, 1995).
NSAIDs appear to inhibit carcinogenesis via the induction of apoptosis in tumor cells (Bedi et al., 1995; Lupulescu, 1996; Piazza et al., 1995; Piazza et al., 1997b). A number of studies suggest that the chemopreventive properties of the NSAIDs, including the induction of apoptosis, is a function of their ability to inhibit prostaglandin synthesis (reviewed in DuBois et al., 1996; Lupulescu, 1996; Vane and Botting, 1997). It is hypothesized that this may be effected by the inhibition of cyclooxygenase (COX) activity, which suppresses the synthesis of proinflammatory prostaglandins (Hinz et al., 1999). Epidemiological and laboratory studies suggest that colon carcinogenesis is, at least in part, mediated through modulation of prostaglandin production by COX isozymes (COX-1 and -2) (Kawamori, T., et al. 1998). Recent studies, however, indicate that NSAIDs may inhibit carcinogenesis through both prostaglandin-dependent and -independent mechanisms (Alberts et al., 1995; Piazza et al., 1997a; Thompson et al., 1995; Hanif, 1996). Sulindac sulfone, a metabolite of the NSAID sulindac, lacks COX-inhibitory activity yet induces apoptosis in tumor cells (Piazza et al., 1995; Piazza et al., 1997b) and inhibits tumor development in several rodent models of carcinogenesis (Thompson et al., 1995; Piazza et al., 1995, 1997a). It is hypothesized that a potential mechanism of sulindac activity may be the direct or indirect inhibition of tyrosine kinase (Winde et al., 1998), rather than the COX inhibition of the other NSAID agents.
Several NSAIDs have been examined for their effects in human clinical trials. A phase IIa trial (one month) of ibuprofen was completed and even at the dose of 300 mg/day, a significant decrease in prostoglandin E2 (PGE2) levels in flat mucosa was seen. A dose of 300 mg of ibuprofen is very low (therapeutic doses range from 1200-3000 mg/day or more), and toxicity is unlikely to be seen, even over the long-term. However, in animal chemoprevention models, ibuprofen is less effective than other NSAIDs. Studies have suggested a beneficial effect of the NSAID, aspirin, on colon cancer incidence, with effects being evident only at a weekly total dose of 1000 mg or greater (Giovannucci et al., 1996). However, three large cohort studies have produced conflicting reports on the beneficial effect of aspirin (Gann et al., 1993; Giovannucci et al., 1996; Greenberg et al., 1993). One group of investigators has recently shown that PGE2xcex1 can be decreased at a dose between 80 and 160 mg/day. In contrast, another group of investigators have shown no such effect on colon mucosal prostaglandins at these low doses of aspirin, although substantial education of prostaglandins in upper gastrointestinal mucosa was demonstrated. The results of these studies indicate that a dose of aspirin of 80 mg is at the threshold of effect of this agent on colon mucosa. Thus, aspirin is not generally recommended for the primary chemoprevention of colorectal cancer in the general population due to questions regarding its efficacy coupled with significant risks of serious cerebrovascular and gastrointestinal adverse effects associated with long-term aspirin use (Singh, 1998).
The NSAID piroxicam is the most effective chemoprevention agent in animal models (Pollard and Luckert, 1989; Reddy et al., 1987; Ritland and Gendler, 1999), although it demonstrated side effects in a recent IIb trial. A large meta-analysis of the side effects of the NSAIDs also indicates that piroxicam has more side effects than other NSAIDs (Lanza et al., 1995). In addition, it has been suggested in at least one study that while tumors of the upper gastrointestinal tract are susceptible to pyroxicam treatment, those of the duodenum and colon are relatively resistant (Ritland and Gindler, 1999). Sulindac has been shown to produce regression of adenomas in Familial Adenomatous Polyposis (FAP) patients (Muscat et al, 1994), although at least one study in sporadic adenomas has shown no such effect (Ladenheim et al., 1995).
2. DFMO
xcex1-Difluoromethylornithine (DFMO) is an enzyme-activated, irreversible inhibitor of ornithine decarboxylase (ODC) and causes depletion in the intracellular concentrations of putrescine and its derivative, spermidine (Pegg, 1988). Levels of spermine, which is derived from spermidine, are not as markedly affected by the enzyme inhibition. DFMO was initially synthesized for therapeutic anticancer usage, but it was found not to be an active cytotoxic agent in chemotherapy trials against human cancer (McCann and Pegg, 1992), except perhaps demonstrating moderate activity in the treatment of malignant brain tumors (Levin et al., 1987). In general, the compound was nontoxic, with the significant exception of hearing loss, which was reversible after the drug treatment was discontinued (Meyskens et al., 1986). The onset of the hearing loss could be associated with total cumulative dose (Croghan et al., 1991).
In experimental animal models, DFMO is a potent inhibitor of carcinogenesis that is especially active in preventing carcinogen-induced epithelial cancers of many organs, including those of the colon (Weeks et al., 1982; Thompson et al., 1985; Nowels et al., 1986; Nigro et al., 1987). DFMO acts late in the tumor-promotion phase in animals, but the precise mechanism by which it inhibits the development of polyps and cancers is unknown. Effects on cell transformation, invasion, and angiogenesis by ornithine decarboxylase and polyamines have been reported (Auvinen, 1997); for example, overexpression of ODC enhances cellular transformation and invasion (Kubota et al., 1997).
The combination of DFMO and piroxicam has been shown to have a synergistic chemopreventive effect in the AOM-treated rat model of colon carcinogenesis (Reddy et al., 1990), although DFMO exerted a greater suppressive effect than piroxicam on Ki-ras mutation and tumorigenesis when each agent was administered separately (Singh et al., 1993; Reddy et al., 1990; Kulkarni et al., 1992). In one study, administration of DFMO or piroxicam to AOM-treated rats reduced the number of tumors harboring Ki-ras mutations from 90% to 36% and 25% respectively (Singh et al., 1994). Both agents also reduced the amount of biochemically active p21 ras in existing tumors. (Singh et al., 1993). Despite the success of the drugs in model systems, phase I trials conducted with this combination resulted in a range of adverse side effects (Carbone et al., 1998).
Studies have also been conducted in which DFMO was combined with aspirin to evaluate its chemopreventive effect in to AOM-treated rats. The combination of aspirin and DFMO administered after AOM was found to be synergistic (Li et al., 1999). The results demonstrated that the aspirin and DFMO combination could prevent colon cancer when administered after AOM (Li et al., 1999).
There remains a need for effective and less toxic methods for treating cancers. Current treatment protocols, especially those for colon cancers and polyps, include tumor resection, chemotherapy and radiation therapy. Colorectal cancer is the second leading cause of death from cancer in The United States.
Accordingly, it is the object of the present invention to provide a novel method for preventing and/or treating cancer in a patient comprising administering an effective amount of difluoromethylornithine (DFMO) in combination with celecoxib.
It is another object of the present invention to provide a novel method for preventing and/or treating cancer in a patient comprising administering a dose of DFMO of about 0.05 to about 5.0 gm/M2/day, and preferably 0.05 to about 0.50 gm/M2/day and a dose of celecoxib of about 10 to 1500 mg/day, and preferably 100 to 400 mg/day.
It is another object of the present invention to provide a novel method for preventing and/or treating cancer in a patient, wherein the cancer is colon cancer, breast cancer, pancreatic cancer, brain cancer, lung cancer, stomach cancer, a blood cancer, skin cancer, testicular cancer, prostate cancer, ovarian cancer, liver cancer, esophageal cancer, familial adenomatous polyposis.
It is another object of the present invention to provide a novel method for preventing and/or treating cancer in a patient comprising administering an effective amount of difluoromethylornithine (DFMO) in combination with celecoxib to said patient wherein DFMO is administered prior to celecoxib, wherein DFMO is administered after celecoxib, wherein DFMO is administered at the same time as celecoxib, wherein DFMO is administered at least a second time, or wherein celecoxib is administered at least a second time.
It is another object of the present invention to provide a novel method for preventing and/or treating cancer in a patient, following resection of a solid tumor, wherein DFMO and celecoxib are administered prior to said resection or are administered after said resection.
It is another object of the present invention to provide a novel method for preventing and/or treating cancer in a patient, wherein the DFMO and celecoxib are administered directly to said tumor, are administered systemically, are administered into the regional vasculature of said tumor, are administered into the region lymph system of said tumor, or are administered by different routes.